6-fluoro pregnanes and intermediates therefor



United States ater fiice Pa tented Sept. 6, 1960 G-FLUORO PREGNANES ANDINTERMEDIATES 5 THEREFOR No Drawing. Filed July 21, 1958, Ser. No.749,652

Claims priority, application Mexico July 20, 1957 15 Claims. c1.zen-239.55

The present invention relates to cyclopentanophenanthrene derivativesand to a process for the production thereof.

More particularly the present invention relates to 60L- fluoro 9uhalo(bromo, chloro or fluoro) derivatives of cortisone, hydrocortistone,l-dehydro-cortisone and l-dehydro-hydrocortisone, as well as to their21-esters with hydrocarbon carboxylic acids of less than 12 carbonatoms. The compounds just referred to are valuable glucocorticoidhormones having anti-inflammatory prop erties and may be administered byall of the methods and in well known combinations with pharmaceuticalcarriers. The present invention also relates to certain novel methodsfor the production of these compounds and to novel intermediates. 7

In our US. patent application Serial No. 740,550, filed June 9, 1958,there is disclosed the novel cortical hormone 6u-fluorohydrocortisoneand its 21-esters. In accordance with one of the methods of the presentinvention it has been discovered that the ZI-esters of 6a-flll01'0-hydrocortisone, and especially the ZI-acetate, may be used as a startingmaterial for the production of the novel 9a-halo compounds previouslyreferred to. Thus upon dehydration with thionyl chloride an additionaldouble bond at C-9(l1) is produced to give the novel intermediate i.e.the Zl-acetate of 6-fluoro-A -pregnadien-l7a,2l-diol-3,20-dione.Addition of hypobromous acid to the double bond then gave the ZI-acetateof 6afluoro-9a-bromo-hydrocortisone. This compound is a key intermediatein the process since it may be converted to its l-dehydro derivative byreaction with selenium dioxide and to the corresponding 9a-Chl010 and9u-fluoro compounds by conversion to the intermediate 95,116- oxidoderivative. The same sequence may also be applied to the 6a-fluoroprednisolone acetate of the previously mentioned prior application.Another novel method for the production of the compounds of the presentinvention involves starting with the ZI-acetate of cortisone, 9a-fluorocortisone or 9a-fluoro hydrocortisone, converting these compounds totheir enol acetates and treating the enol acetates with sodiumborohydride to selectively reduce the -keto group, saturate the C-3 (4)double bond and hydrolyze the ester groups. Reesterification to thetetraacetate of A -pregnen-3fi,l7a,20,2l-tetro1-1l-one (or its9oc-fl11010 or chloroanalogues) and epoxidation gave the corresponding5a,6a-epoXide. The epoxide ring was then opened with boron tn'fluorideetherate to give the corresponding 3,17,20,21-tetracetate of6B-fluoropregnan 3fi,5oc,17oc,20,21 pentol l1 one. The acetyl groups atC-3, 20 and 21 were preferentially saponified, and the hydroxyl group at0-21 preferentially acetylated to give the 17,21-diacetate. Thisdiacetate was then oxidized to give the corresponding 17,21-diacetate of'65- fluoro-pregnan-5a,17a,2l1-triol-3,11,20-trione (or its 9achloro orfiuoro derivatives). Treatment of these last compounds with dry hydrogenchloride in acetic acid solution dehydrated at 0-5 and inverted theGfl-fluoro to 60a to produce the 17,21-diacetate of oa-fluoro-cortisoneor its 9o-halo (chloro or bromo) derivatives. If the dehydra tion waspreformed with thionyl chloride the diacetate of 6B-fluoro-c0rtisone orits 9u-ha1o derivatives (chloro or bromo) was formed.

Certain of the novel compounds of the present inven-* tion may beillustrated by the following formulas:

011,02 ornonc l f I 0: O:

GH OAc onion ore In the above formulas X represents=0 and Z represents adouble bond between 0-1 and 0-2 or a saturated linkage. Y representschloro, bromo or fluoro, R represents hydrogen or a hydrocarboncarboxylic acid acyl group of less than 12 carbon atoms which may besaturated or unsaturated, straight or branched chain aliphatic, cyclicor mixed cycloic-aliphatic and may be substituted conventionally as byhalogen. Typical acyl groups of this type are acetate, propionate,cyclopentylpropionate, benzoate, caproate, tn'methylacetate,phenoxypropionate and fi-chloropropionate. Ac represents acetate. Rrepresents hydrogen, chloro or fluoro.

One of the process for the production of the compounds of the presentinvention may be illustrated by the following equation.

CHflOAG GHzOAc do to thionyl chloride selenium Addition dioxide of HOB!thionyl chloride k F F Addition Addition of ofHOBr HOlor HF potassiumselenium acetate dioxide CHaOR diene, for example by treatment of itsdioxane solution with N-bromoacetamide and perchloric acid, to producethe ZI-acetate of 6ot-fluoro-9a-bromo-hydrocortisone. Oxidation of thehydroxyl group at 0-11, for example with chromic acid in aqueous aceticacid solution, produced the 21-acetate of 6et-fluoro-9a-bromo-cortisone.

For the introduction into these compounds of an additional double bondbetween 0-1 and 0-2, they were refluxed with selenium dioxide,preferably in mixture with t-butanol, in the presence of pyridine andunder an atmosphere of nitrogen.

Starting from the ZI-acetate of 6a fluoro 9oz bromohydrocortisone, therewas thus obtained the 21-acetate of 6a-fluoro-9a-bromo-prednisolone. Thetreatment of the 21-acetate of 60a fluoro 91x bromo cortisone withselenium dioxide produced the 2l-acetate of 60a fluoro-9a-bromo-prednisone.

In turn, the Zl-acetateof 6wfluoro 9' bromo-hydrocortisone is the keycompound for preparing other 6afluoro 9oz halo compounds such as theill-acetates of 6a-fluoro-9ut-chloro-hydrocortisone and of6u,9tx-difluorohydrocortisone.

The 2l-acetate of 6a-fluoro-9u-bromo-hydrocortisone was refluxed inethanol solution With anhydrous potassium acetate to form the Zl-acetateof 6a-fluoro-9B, llfioxido-A -pregnen-17u,21-diol-3,2O-dione; by theaddition of the elements of hydrogen chloride, this oxide-compound wasconverted into the 2l-acetate of 6zx-flIlOIO-9oc-Chl0l0- hydrocortisone,while reaction with hydrogen fluoride led to the formation of the2l-acetate of 6a,9ot-difluoro-hydrocortisone. The reaction with thehydrogen halides was preferably carried out in chloroform solution, atlow temperature and under anhydrous conditions.

By a similar method of oxidation to that of the 21- acetate of6u-fluoro-9a-bromo-hydrocortisone, we also oxidized these 9a-chloro and9oc-flll010 compounds to convert the hydroxyl group at 0-11 to a ketogroup, and thus we obtained the ZI-acetates of6a-fluoro-9lz-chlorocortisone and of 60:,9ot-diflll0IO-C0ltl80l16.Dehydrogenation of these compounds afforded the corresponding dihaloderivatives of prednisone. It is obvious that the oxidation of the11,8-hydroxyl group can also be carried out as a final operation, thatis, after the dehydrogenation, to convert the prednisolone derivativesinto those of prednisone.

As mentioned before, We used the ZI-acetate of 6afluoro-hydrocortisoneas the starting material for the.

present invention. Now, alternatively, instead of first carrying out thedehydration of this compound, the introduction of the additional doublebond between C-1 and C-2 can be efiected first and then the halogen atomat C-9u introduced. Dehydration of 6a-fluoro-prednisolone with thionylchloride yielded the corresponding 1,4,9(11)- triene. By the methoddescribed previously, the reaction with N-bromoacetamide gave the21-acetate of 6OL-flll0l'0- Qa-bromo-prednisolone, which upon treatmentwith potassium acetate furnished the corresponding 95,1116- epoxide.Reaction of the latter with hydrogen chloride or fluoride produced,respectively, the ZI-acetate of 60afluoro-9u-chloro-prednisolone and of6a,9a-difluoro-prednisolone, identical to the compounds obtained byhalogenation of 6a-fluoro-hydrocortisone and subsequent introduction ofthe additional doublebond between C-1 and The 2l-acetoxy groups of the6oz-flllOI0-9oz-halO compounds thus prepared were saponified, preferablyby reaction With sodium methoxide under an atmosphere of nitrogen, toform the corresponding 21-hydroxy compounds, which in turn wereconventionally reesterified to produce the corresponding 21-esters ofhydrocarbon carboxylic acids of less than 12 carbons of' the novel 6c:-fluoro-9vt-halo derivatives as previously set forth. The esterlficationat C-2l was preferably carried out by reaction with anhydrides orchlorides of such acids in pyridine solution.

acetic anhydride p-toluenesulfonic acid l reduction an acetylation CHOAc IHOAC CHgOAO CHOAO -"O Ac 0A0 0- 0 R peracid I AcO I AcO borontrifluoride partial saponification AcO- I acetylation I oxidation 0H Fdry thionyl CHzQR I O "-zOR o=/\ dry H01 0= 0= In the above formula Ac,R and R represent the same groups as heretofore set forth.

In practicing the process above set forth the 21-acetate of cortisone,or of 9oc-Ch10l'O-COI'liSOI1e or of 9a-fluorocortisone (R is hydrogen,chloro or fluoro) is treated with acetic anhydride in the presence ofp-toluenesulfonic acid to form the corresponding enol triacetateindicated in the equation. The keto group at 0-20 of these compounds wasselectively reduced, the double bond between C-3 and C-4 was saturatedand the acetyl groups at C-3 and 0-21 were hydrolyzed, all in one step,by reaction with sodium borohydride in methanol solution. The freehydroxyl groups were then acetylated and thus there was prepared thecorresponding tetraacetates of A -pregnen- 3/3,17a,20,21-116iIOl1-1-OI1Band the 9aohloro and 9afluoro derivatives thereof.

The double bond of the tetraacetate of A -pregnen-3fi,17u,20,21-tetrol-11-one or its corresponding 9u-halo analogue wasexpoxidized to form. the corresponding 5a,6u-epoxide. The epoxide ringwas now opened by re-.

action with boron trifluoride etherate and thus we obtained the3,17,20,21-tetraacetate of the corresponding 65 fluoro-pregnan-3B,5u,17oc,20,21-P6I1110l-1 l-one. The acetyl groups at C-3, 20 and 21 werepreferentially saponified by reaction with perchloric acid in methanolsolution, the hydroxyl group at 0-21 was preferentially eacetylated byreaction with 1.1 mols of acetic anhydride at low temperature and thefree hydroxyl groups of the resulting 17,21-diacetate of6B-fluoro-pregnan- 3B,5a,l7a,20,2l-pentol were oxidized to form the17,21- diacetate of the corresponding 6 3-fluoro-pregnan-5ad7u, 2l-triol-3,1 1,20-trione.

Treatment of these last mentioned compounds with dry hydrogen chloridein acetic acid solution caused the dehydration at G5 with simultaneousinversion of the steric configuration of the fluorine atom to producethe 17,21- diacetate of 6a-fiuoro-cortisone or its 9a-halo homologuesabove shown.

Alternatively, the 6B-fluoro preg-nan-5m,17a,2l-triol- 3,11,20-trionederivatives were treated in pyridine solution with thionyl chloride at atemperature of around 0 C., and thus we achieved the dehydration withoutsimultaneous inversion of the steric configuration of the fluorine atom,to produce the diacetate of the corresponding 6/i-fluoro-cortisone.

Treatment of this diacetate in acetic acid solution with dry hydrogenchloride caused its conversion into the diacetate of 6a-fluoro-cortisoneor its corresponding 91:- halo analogue.

Finally, the 17,21-diacetate of 6fi-fluoro-pregnan-5a, l7a,2l-triol-3,'1l,20-t1ione, or its 9a-halo analogue, were converted into6,8-fluoro-cortisone or its 9a-halo-analogues by treatment withmethanolic potassium hydroxide, since this dehydration is accompanied bythe hydrolysis of the acetylated groups.

The acetoxyl groups of the 6a-fluoro and 6fl-fluoro derivatives ofcortisone and its 9a-halo homologues were hydrolyzed, preferably byreaction with methanolic potassium hydroxide, since this dehydration isaccompanied by the hydrolysis of the acetylated groups.

The \acetoxyl groups of the 6a-fluoro and Gfl-fluoro derivatives ofcortisone and its Qua-halo homologues were hydrolyzed, preferably byreaction with methanolic potassium hydroxide, to form the correspondingfree diols.

Furthermore, we prepared at 21-esters of the 6/8-fluorocortisone and its9a-halo homologues by conventional methods, which esters were preferablythose derived from hydrocarbon oarboxylic acids having less than 12carbon atoms.

The following specific examples serve to illustrate but are not intendedto limit the present invention.

Example I A solution of 5 g. of the 21-acetate of6a-fluoro-hydrocortisone in 50 cc. of pyridine was cooled to 0 C. andtreated dropwise under stirring with 5 cc. of thionyl chloride, takingcare that the temperature of the mixture did not rise over 0 C. Themixture was stirred for 24 hours further at 0 C. and then it was pouredinto ice water and extracted with ethyl acetate. The extract was washedwith water, dilute hydrochloric acid, 5% sodium carbon-ate solution andagain with water, dried over anhydrous sodium sulfate and evaporated todryness under reduced pressure. Crystallization of the residue fromacetone-hexane yielded the 21-acetate of oa-fluoro-Apregnadien-il7a,21-diol-3,20-dione.

A solution of 2.5 g. of this diene in 25 cc. of pure dioxane containing4 cc. of 0.4 normal perchloric acid was treated at room temperature andin the absence of light with 1.2 g. of N-bromoacetarnide which was addedunder stirring in the course of one hour. The mixture was stirred forone hour further and treated with 10% sodium sulfite solution until thetest with starch-potassium iodide paper failed to give a blue color. 30cc. of chlo- Example II A solution of 2.5 g. of the 2 l-acetate of6oz-fiuoro-9abromo-hydrocortisone in 10 cc. of, dioxane was slowly addedto' a mixture of 1.6 g. of anhydrous potassium acetate and 20 cc. ofabsolute ethanol which was previously heated to the boiling point. Themixture was refluxed for 45 minutes, cooled and diluted with 50 cc. ofice water, under stirring. The precipitate was collected by filtration,washed with water and dried, thus giving the ZI-acetate of6oa-fluoro-9fi,llfi-oxido-M-pregnen-l711,211- diol-3,20-dion'e.

2 g. of this epoxide was dissolved in 20 cc. of pure chloroform, cooledto C. and mixed under stirring with 4 cc. of a 0.5 normal solution ofdry hydrogen chloride in chloroform, while the mixture was maintained at0 C. The mixture was stirred for one hour at the same temperature andthen poured into water. The chloroform layer was separated and washedwith water, sodium carbonate solution and Water, dried over anhydroussodium sulfate and evaporated to dryness under reduced pressure.Crystallization of the residue from acetone furnished the 21-acetate of6a-fluoro-9a-chlorohydrocortisone.

Example III In a polyethylene flask, fitted with a mechanical stirrer,there was dissolved 2.5 g. of the 21-acetate of 6oz-flll010- 95,11Boxido-A -pregnen-17a,21-diol-3,20-dione, obtained as described inExample II, in 40 cc. of pure chloroform. The solution was cooled to 0C. and mixed in the course of 20 minutes, with stirring, with" 0.4 g. ofanhydrous hydrogen fluoride. The mixture was stirred for 2 hours at 0 C.and then neutralized by the addition of aqueous sodium bicarbonate.

The reaction mixture was transferred to a separatory funnel, washed withwater and concentrated under reduced pressure until a bulky precipitateseparated. The mixture was cooled and the precipitate was collected andredissolved in cc. of hot ethyl acetate. The solution was filtered fromsome insoluble material and cooled, thus yielding the 2l-acetateOf60:,9cc-difl1101'0-hYdI'OCO1fisone.

Example IV A mixture of 1 g. of the above compound, 50 cc. of anhydroust-butanol, 300 mg. of selenium dioxide and 0.1 cc. of pyridine wasrefluxed under an atomsphere of nitrogen for 70 hours, cooled andfiltered through celite after dilution with ethyl acetate. The filterwas well washed with ethyl acetate and the filtrate and washings werecombined and evaporated to dryness under reduced pressure. The residuewas triturated with water and the precipitate was collected, dried andpurified by chromatography, thus producing the Zl-acetate of 604,90:-difluoro-prednisolone.

By the same method there was introduced an additional double bondbetween C1 and C2 into the 6ot-fluoro-9abromo and Got-fillOIO-Qoc-ChlOIOderivatives of hydrocortisone, obtained as described in Examples I andII, to produce the Zl-acetates of 6a-fluoro-9a-br'omoprednisolone and6oc-flu0IO-9oa-Chl01'0 prednisolone, respectively.

Example V 5 g. of the ZI-acetate of 6a-fluoro-prednisolone was treated,in pyridine solution, with thionyl chloride and the product of thisdehydration was worked: up in exactly the same way as described inExample I for these steps. There was thus obtained the ZI-acetate of6a-fluoro- A -pregnatrien-l7a,2l-diol-3,20-dione.

Subsequently, there were applied to this compound the reactions ofExamples I, H and III, namely the reaction with N-bromoacetamide, theformation of the epoxide and the introduction of chlorine or fluorine atC9oc. There were thus obtained the 21-acetates of 6a-fluoro-9ubromo-pred'nisolone, of 6a-fluoro-9/8,1lfl-oxido-Apregnadien-17oz,2l-diol-3,20-dione, or" 6oc-fluO1O-9a-chl0IO-prednisolone and. of 6a,9u-difiuoro-prednisolone, respectively.

Example VI A solution of 1 g. of the 21-acetate offioc-flllOl'O-9utbromo-hydrocortisone, obtained in accordance withExample I, in 30cc. of acetic acid was treated under stirring and at atemperature below 20 C. with a solution of 150 mg. of chromiumtrioxid'e' in 6 cc. of acetic acid, which was added dropwise. Themixture was kept standing at room temperature for 2 hours and thenpoured into ice water. The precipitate was collected by filtration,washed with water, dried and recrystallized from acetone-hexane, thusyielding the 21-acetate of 6a-fluoro-9a-bromo-cortisone; Dehydrogenationof this compound by the action of selenium dioxide, as described inExample IV, furnished the 2l-acetate of 6oa-flll01'0-9u-bromo-prednisone.

By the same method there were oxidized and dehydrogenated the6afiuoro-9oc-chloroand 6cx,9a-difluoro clerivatives of hydrocortisone,obtained in accordance with Examples H and III, to give thecorresponding derivatives of cortisoneand prednisone, respectively.

By'thes'am'e method of oxidation described above, the 2l acetatesof the6a,9oc-diha l0 derivatives of prednisolone were converted intothose ofprednisone, namely the 21- acetate of 6u-fiu'oro-91x-bromo-prednisone,the'2l-acetate 6a,9a-difluoro-prednisone, respectively.

Example VII A solution of 1 g. of the ZI-acetate of6u,9u-difluoroprednisone in 200icc. of methanol was cooled to 0 C. andmixed with mg. of sodium methoxide, under an atmosphere of nitrogen andtaking care that the temperature was maintained at 0 C. After 15 minutesat 0 C., the mixture was neutralized with acetic acid, evaporated todryness under vacuum and the residue was triturated with water. Theprecipitatewas collected and recrystallized from acetone, thus producingthe. free 6a,9u-difluoro-prednisone.

By a similar method there were saponified the 21- a'cetoxy groups of allof the 6ot-fll10l'O-9oc-halO compounds obtained in accordance with theprevious examples to form the corresponding. 2l-hydroxy compounds.

Example VIII A mixture of 1 g. of the free 6a-fluoro9a-chloro-'prednisolone, 20 cc. of pyridine and 1 cc. of propionic anhydride'waskept standing overnight at room temperature and then poured into icewater. The product was extracted with ethyl acetate and the extract wassuccessively washed with water, dilute hydrochloric acid, water, sodiumbicarbonate solution and water, dried over an hydrous sodium sulfate andevaporated to dryness. The

cifically therewere prepared the 21'-acetates, propionates,

cyclopentylpropi'onates' and benzoates Example IX 3 g. ofp-toluenesulfonic acid was added to a solution of 5 g. of the 21-acetateof cortisone in 250 cc. of acetic anhydride and the mixture was keptstanding for 70 hours at room temperature with occasional stirring. Itwas then poured into water, the precipitate was filtered, washed toneutral, air dried and crystallized from methanol, thus giving thetriacetate of A -pregnadien-3,17a, 21-triol-11,20-dione.

4 g. of this tr-iol-dione was dissolved in 200 cc. of methanol, cooledin an ice bath and slowly mixed with constant stirring with a solutionof 2 g. of sodium borohydride in 20 cc. of water, while the temperaturewas maintained below C. The stirring was continued at this temperaturefor 2 hours further and the mixture was neutralized with acetic acid,concentrated under reduced pressure to a volume of 30 cc. and dilutedwith 200 cc. of water; the precipitate of the 17-acetate of A-pregnen-3fi,l7u,20,21-tetrol-1l-one was filtered, dried, dissolved incc. of pyridine and treated with 4 cc. of acetic anhydride. Afterkeeping the mixture overnight at room temperature it was poured intowater and the precipitate was filtered and recrystallized from acetonehexane, thus giving the tetraacetate of A pregnen-3fl,17u,20,21tetro1-1l-one.

3 g. of the tetraacetate of A -pregnen-3fi,17u,20,2ltetrol-ll-onedissolved in 300 cc. of chloroform was mixed with 1.5 mols ofmonopenphthalic acid in ether 1 7 solution and then kept at roomtemperature for 20 hours. Water was added, the organic layer wasseparated and washed with water, sodium bicarbonate solution and againwith Water, dried over anhydrous sodium sulfate and evaporated todryness under reduced pressure. There was thus obtained the crudetetraacetate of 511,60; oxido pregnan 3j3,17a,20,2l tetrol 11 one whichwas purified by recrystallization from aceto-nehexane.

A solution of 3 g. of this tetraacetate in 150 cc. of ether and 150 cc.of benzene was treated with 3 cc. of boron trifiuoride etherate whichwas added slowly under stirring; the mixture was stirred for 3 hoursfurther at room temperature and then washed with water, sodiumbicarbonate solution and water, dried over anhydrous sodium sulfate andevaporated to dryness, thus leaving as a residue the crude3,17,20,21-tetraacetate of 61S fluoro pregnan 3}9,5ot,17oc,20,21 pentol11- one which was used for the next stage without further purification.

The tetraacetate of this 6fi-fluoro pen-tolone was mixed with 50 cc. ofa 0.2 normal solution of perch-loric acid in methanol and refluxed for 2hours, cooled and diluted with water. The precipitate was collected,washed with water and dried in vacuum, thus giving the crude 17- acetateof 6fi-fluoro-pregnan-3pfiu,17a,20,21-pentol11- one.

This monoacetate was dissolved -in 20 cc. of pyridine, cooled to 0 C.,treated with 1.1 mols of acetic anhydride and kept standing for 18 hoursat 0 C. and then for 2 hours at around C. The mixture was poured intowater, the product was extracted with ethyl acetate and washed withwater, dilute hydrochloric acid and water, dried over anhydrous sodiumsulfate and evaporated to dryness. The residue consisted of the crude17,21-diacetate of 6fifluoro-pregnan-3/3,5u,17a,20,21-pentol-11- one.

3 g. of the crude 17,21-diacetate of GB-fiuoro-pregnan-3p,5a,17a,20,21-pentol-1l-one was dissolved in 150 cc. of acetone,cooled to 0 C. and treated dropwise under stirring at 0 C. with anoxidizing reagent prepared with 1.6 of chromium trioxide, 1.4 cc. ofsulfuric acid and 2 cc. of water. The reagent was added in the course of2 minutes and the stirring was continued for an hour at 0 C. Afterdiluting with water the product was extracted with ether and the extractwas washed with water, dried over anhydrous sodium sulfate, filtered andevaporated to dryness. There was thus obtained the 17,2l-di acetate of6fi-fluoro-pregn-an-5a,l7u,21-triol-3,11, 20-t-rione in crude form.

The above diacetate was dissolved in 100 cc. of glacial acetic acid anda slow stream of dry hydrogen chloride was passed into the solution for2 hours at a temperature of around 18 C. and then it was diluted withwater. The product was extracted with ethyl acetate, washed with water,5% sodium carbonate solution and water, dried over anhydrous sodiumsulfate, filtered and evaporated to dryness. The residue consisted ofthe crude diacetate of 6a-fluoro-cortisone which was purified byrecrystallization from acetonehexane.

3 g. of the crude diacetate of 6a-fluoro-cortisone was dissolved in 30cc. of 1% methanolic potassium hydroxide and kept for 2 hours at 0 C.under an atmosphere of nitrogen. The mixture was neutralized with aceticacid, diluted with water and extracted with ethyl acetate; the extractwas washed with water, dried over anhydrous sodium sulfate andevaporated to dryness. Crystallization of the residue fromacetone-hexane yielded 6a-fluorocortisone.

Example X A solution of l g. of the crude 17,21-diacetate of6B-fluoro-pregnan-5a,l7u,21-triol-3,11,20-trione, obtained in accordancewith the previous example, in 10 cc. of pyridine was cooled to 0 C. andtreated dropwise under stirring with 1 cc. of thionyl chloride, takingcare that the temperature did not rise over 0 C. The mixture was stirredfor a further 2 hours at 0 C. and then poured into water. The productwas extracted with ethyl acetate, washed with dilute hydrochloric acid,5% sodium carbonate solution and again with water to neutral, dried overanhydrous sodium sulfate and evaporated to dryness. The residueconsisted of the crude 17,21-diacetate of 6B-fiuoro-cortisone which waspurified by crystallization from acetone-hexane.

This crude diacetate was dissolved in acetic acid and treated with dryhydrogen chloride such as has been described in the previous example,thus achieving the inversion of the steric configuration of the fluorineatom to give the diacetate of 6u-fluoro-cortisone, identical to the oneobtained in accordance with the previous example.

Example XI 1 g. of the crude 17,21-diacetate ofSB-fluQro-pregnan-5a,17a,21-triol-3,11,20-trione, obtained in accordancewith Example IX, was treated with 30 cc. of 1% methanolic potassiumhydroxide by the method described in that example, thus effecting thedehydration at C-5 and the hydrolysis of the acetylated groups to give65- fluoro-cortisone.

Example XII The treatment of the diacetate of 6,6-fluoro-cortisone,obtained in accordance with Example X, by the method of the previousexample afforded 6B-fluorocor-tisone, identical to the one obtained inaccordance with the previous example.

Example XIII When the starting cortisone was substituted by its chloroor its 9cc-flll0l0 analogs, respectively, and following the methodsdescribed in the previous Examples 'IX to XII, there were obtained thefollowing intermediates: the triacetates of 9c: chloro A pregnadien3,17a, 2l-triol-ll,20-dione and of 9a-fluoro-A -pregnadien-3,17a,2l-triol-11,20-dione; the tetraacetates of 90b-Ch1OTO A pregnen3B,17x,20,21 tetrol 11 one and of 9afluoro A pregnen 3{3,17a,20,21tetrol 11 one; the tetraacetates of9a-chloro-5a,6a-oxido-pregnan-3fl,17e,20, Zl-tetrol-ll-one and of9a-fluoro-5a,6ot-oxido-pregnan- 3B,17a,20,21 tetrol 11 one; the3,17,20,21 tetraacetates, l7-mo-noacetates and 17,21-diacetates of 6p-11 fluoro 9a chloro pregnan 3fi,5a,17u,20,2l pentol- 1:1-one and of6,8,9a-difluoro-pregnan-3pja,17u,20,21- pent'ol -ll-one; the17,21-diacetates f 6flfluoro-'9a-chlomO-pregnan-Sa,17a,21-triol-3,11,20trione and of 6 8,90:-difiuoro-pregnan-S 17a,21-triol-3,l1,20-trione; as well as the;diacetates of 6,8-fluoro-9a-chloro cortisone, Got-fluoro-9w6hl'01'0-COI'tiS0n6, 6/3,9u-difluoro-cort-isone and of 60a,9a-difluor'o-cortis'one. The final compounds were 60:- fluoro 9a ohlorocortisone, 60,9a difluoro cortisone, 6/9-fluoro-9a-chloro-cortisone and613,9oc-difi110rO-" cortisone.

Example XIV A solution of 1 g. of 6B-fluoro-cortisone in 10 cc. ofpyridine was mixed with 0.5 g. of acetic anhydride and kept at roomtemperature for 4 hours. The mixture was poured into water, heated forhalf an hour on the steam bath and cooled. The precipitate was collectedand crystallized from acetone-hexane, thus giving the 21- acetate of6,8-fiuoro-cortisone.

When acetic anhydride was substituted by the anhydride 0r chloride ofanother hydrocarbon carboxylic acid,

namely propionic, cyclopentylpropionic, benzoicetc.,.

3. The tetraacetate of 9a-fluoro-5a,6a-oxido-pregnan- 3 ,8,17a,20,21-tetrol-1 l-one.

4. The 3,17,20,21-tetraacetate of 6 3-fluoro-pregnan-3y3,5a,17a,20,21-pentol-ll-one.

5; The 3,17,20,21'-tetraacetate of apsa-difluoro-pregnan-313,50,17,20,21*pentol-1 l-one.

6. The 3,17,20,21-tetraacetate of6fl-fluoro-9d-chlofopregnan-3B,5a,17a,20,21-pent01-1 l-one.

7. The 17-mono acetate of 6B-fluoro-pregnan-3;3,5a,17a,20,21-pentol-11-one.

8. The 17-mono acetate of 6 3,9a-difluoro-pregnan-3fl,5a,17a,20,2l-pentol-l l-one. I

9. The 17-mono acetate of fi-fluoro-9a-ch1oro-pregnan- 38,5a,17a,20,2l-pentol-1l-one. v

10. The17,21-diacetate of 6fi-fluoro-pregnan-3B,5a,17a,20,2l-pentol-11-one.

11. The 17,21'-diacetate of 65,9a-difluoro-prtegnan-SB,5a,17a,20,21-pentol-1l-one.

12. The 17,21-diacetate of 6fi-fiuoro-9u-chloro-p1egnan-3B,5a,17a,20,21-pentol-1l-one.

13. The 17,21-diacetate of 6fi-fluoro-pr'egnan-5a,l7a, 2 l-triol-3 ,11,20-trione.

14. The 17,21-diacetate of 6,8-fluoro-'9'u-chloro'-pregnanc,:,21-t1'iOl-3 ,11,20-trione.

15. The 17,21-diacetate of 6fi,-9a-difluor'o-pregnan-5a,17oc,21-t1'i01-3, 1 1,20-trione.

References Cited in the file of this patent UNITED STATES PATENTS2,837,464 Nobile June3, 1958 2,838,497 Spero et a1. June 10, 19582,838,498 Magerleinet al. June 10, 1958 2,838,499 Spero et a1. June 10,1958 2,841,600 Hogg et a1. July 1, -8

3. THE TETRAACETATE OF9A-FLUORO-5A,6A-OXIDO-PREGNAN3B,17A,20,21-TETROL-11-ONE.
 6. THE3,17,20,21-TRETRAACETATE OF6B-FLUORO-9A-CHLOROPREGNAN-3B,5A,17A,20,21-PENTOL-11-ONE.